Cafe au Lait Spots (Macules)

Background

Café au lait spots, or café au lait (CAL) macules (CALMs), are hyperpigmented lesions that may vary in color from light brown to dark brown (see the images below)^[1] ; this is reflected in the name of the condition, which means "coffee with milk." The borders may be smooth or irregular.

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Axillary freckling showing café au lait spots.

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Multiple irregular sized and shaped café au lait lesions.

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Café au lait lesions.

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Café au lait lesions.

Café au lait skin lesions widely vary widely in size and number and are usually the earliest manifestations of neurofibromatosis.^[2]  The macules may be observed in infancy, though they are typically very light in infants and can be difficult to appreciate. The skin lesions develop in early infancy, and they may enlarge in size and become obvious after age 2 years.

CALMs are observed in 95% of patients with neurofibromatosis type 1 (NF1), which is the neurocutaneous syndrome with which they are most often associated.^[3] These spots may also be observed in patients without NF1. Other conditions in which they may be observed include McCune-Albright syndrome, tuberous sclerosis, Fanconi anemia, and Coffin-Siris syndrome, characterized by developmental delay, speech impairment, distinctive facial features, hypertrichosis, hypoplasia of the distal phalanx of the fifth digit, and agenesis of the corpus callosum.^[4]  CALMs may be a marker for RASopathies, disorders related to RAS mutations.^{[5, 6]}

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Pathophysiology

Café au lait spots are caused by an increase in melanin content, often with the presence of giant melanosomes. A significant increase in melanocyte density is noted in the CALMs of patients with NF1 compared with patients who have isolated CALMs without NF1 involvement. Also, an increase in stem cell factor cytokines is more frequently observed in NF1 CALMs than in non-NF1 CALMs.

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Etiology

CALMs associated with NF1 result from an autosomal dominant disorder with high penetrance and variability in the expression of clinical features.

The NF1 gene is localized to the pericentromeric region of the long arm of chromosome 17. The gene encodes for neurofibromin, which is a GTP-ase activating protein that downregulates the cellular proto-oncogene p21-ras.

About 50% of individuals with NF1 have a spontaneous mutation. This high incidence is thought to result from the large size of the gene, which increases the likelihood of spontaneous mutations.

Occasionally, patients who have larger gene deletions have a higher incidence of intellectual disability and earlier appearance of cutaneous neurofibromas.

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Epidemiology

United States and international statistics

In the newborn period, solitary café au lait spots may occur in 0.3% of Whites, 3% of Hispanics, and in 18% of Blacks.^[7] In childhood, solitary CALMs occur in 13% of Whites and 27% of Blacks. Two or more CALMs were not observed in any of 4000 White newborns but were found in 8% of Black newborns. Café au lait spots that confirm the diagnosis of NF1 occur at an estimated frequency of 1 in 3500 persons.^[8]

Solitary café au lait spots have been reported to occur in 0.5% of Arab newborns and in 0.4% of Chinese newborns.^[7]

Age-, sex-, and race-related demographics

Typically, café au lait spots are present at birth, though they may be difficult to appreciate. A Wood lamp may improve the ability to visualize these faint spots. By the time the child is aged 2-3 years, CALMs are clearly visible. The size and number of CALMs increase with patient age in patients with NF1.

No sexual predilection is recognized.

Café au lait spots are more frequently observed in Black children.

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Prognosis

CALMs have not been demonstrated to undergo malignant change. They are benign and produce no mortality or morbidity, though the syndromes associated with them may have significant manifestations.

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History

The presence of numerous café au lait macules (CALMs) should raise the suspicion of a genetic disorder.^[3] The most common associated systemic disorder is neurofibromatosis type 1 (NF1).

The diagnostic criteria for NF1 are met if two or more of the following are present:

• Six or more café au lait spots larger than 5 mm in their greatest diameter in prepubertal individuals or larger than 15 mm in their greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Optic glioma
• Two or more Lisch nodules (iris hamartomas)
• A distinctive osseous lesion (eg, sphenoid dysplasia or thinning of the long bone cortex), with or without pseudoarthrosis
• A first-degree relative with NF1, according to the above criteria

Characteristics of NF1 in the newborn period include the following:

• Pseudarthroses
• Congenital glaucoma
• Sphenoid wing dysplasia

Characteristics of NF1 in the early childhood period include the following:

• Embryonal tumors
• Compression injuries - Plexiform neurofibromas in the mediastinal cavity may cause compression; back pain in a patient with café au lait lesions should always be taken seriously because it may be a sign of a radiculopathy
• Optic pathway gliomas - These occur by the time the patient is aged 3 years

NF1 should be differentiated from neurofibromatosis type 2 (NF2). NF2 is also referred to as central neurofibromatosis because it is associated with acoustic neuroma. Patients with NF2 may also have CALMs. NF2 is more likely to be diagnosed in middle-aged persons, whereas NF1 is typically diagnosed in children. The genes that are responsible for these twp disorders are on different chromosomes: chromosome 17 for NF1 (encoding neurofibromin) and chromosome 22 for NF2.

Other syndromes associated with café au lait spots include the following:

• McCune-Albright syndrome - This syndrome often has a single large asymmetric CALM with irregular borders, often described as resembling the "coast of Maine"; it is associated with polyostotic fibrous dysplasia, which leads to pathologic fractures, precocious puberty, and numerous hyperfunctional endocrinopathies^[9] ; in early life, it may present with a single large irregular café au lait spot; follow-up observations reveal the endocrine abnormalities
• Fanconi anemia - CALMs are present along with intellectual disability, aplastic anemia, and risk for malignancy.
• Tuberous sclerosis - Café au lait spots are present along with ash leaf spots, facial angiofibromas, hemangiomas, cardiac rhabdomyomas, and shagreen patches
• Silver-Russell syndrome
• Ataxia telangiectasia
• Bloom syndrome
• Basal cell nevus syndrome
• Gaucher disease
• Chédiak-Higashi syndrome
• Hunter syndrome
• Legius syndrome
• Maffucci syndrome
• Multiple mucosal neuroma syndrome
• Watson syndrome

Whereas small café au lait spots are associated with various syndromes, large solitary light-brown patches often represent segmental lentigines that are not associated with any neurocutaneous syndromes or developmental anomalies. Mosaic presentations of neurofibromatosis can also manifest localized café au lait macules or patches.^[10]

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Physical Examination

Café au lait spots are flat lesions that are typically the color made by adding milk to coffee. They may range in size from a few millimeters, as in axillary freckling, to large macules measuring more than 10 cm.

Large solitary CALMs are larger than 0.5 cm. They are found more commonly on the buttocks than in any other anatomic location. No other physical findings or syndromes are usually related to solitary café au lait spots.

Axillary freckling (known as Crowe sign) and inguinal freckling are characteristic diagnostic features of NF1.

Plexiform neurofibromas may underlie CALMs in NF1. These are large fibrous swellings of the subcutaneous tissue that may cause severe disfigurement of the face or limbs.^[11]

Café au lait spots are associated with underlying disorders, and physical findings indicative of those disorders include the following:

• Scoliosis
• Hypoplastic bowing of the legs
• Osseous lesions in the ribs
• Pseudoarthrosis of the tibia
• Spina bifida
• Scalloping of the vertebral body
• Lisch nodules
• Neurofibromas
• Lipomata
• Angiomata
• Ptosis
• Ocular abnormalities (including glaucoma and corneal opacifications)
• Pheochromocytoma

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Laboratory Studies

The presence of multiple café au lait macules (CALMs) should prompt a search for features suggestive of an underlying genetic disorder. Early diagnosis and genetic testing/counseling are important because of the genetic transmission of the underlying systemic disorders, if one is present. Genetic testing is available for the diagnosis of neurofibromatosis type 1 (NF1)-associated CALMs. Guidelines for genetic counseling in patients with NF1 have been established.^[12]

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Procedures

Dermoscopy may aid in distinguishing CALMs from congenital melanocytic nevi in children, including those with darker skin. Shah et al reported two cases in which dermoscopy identified CALMs in a neonate with phototype V skin and a 17-month-old with phototype IV skin.^[13]

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Histologic Findings

Hyperpigmentation of basilar keratinocytes is noted. Giant melanosomes may be present within keratinocytes.

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Medical Care

Café au lait macules (CALMs) do not require medical care. When café au lait spots are associated with neurofibromatosis (NF) or another underlying condition, monitoring of associated conditions is required.

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Surgical Care

Although treatment of these lesions is not necessary, several lasers have been used to treat CALMs, with varying results.^{[14, 15, 16, 17, 18, 19]}  The types most commonly used are probably the double-frequency (532 nm) neodymium-doped:yttrium aluminum garnet (Nd:YAG) laser, the 694-nm ruby laser, the 755-nm alexandrite laser, and the 1064-nm Nd:YAG laser.^[20]  The risks of laser procedures must be discussed with the patient and the family. Possible adverse effects include transient hyperpigmentation, hypopigmentation, slight scarring, permanent hyperpigmentation, and recurrence. Laser therapy has become the mainstay of treatment for CALMs.^[20]

In 2017, a retrospective study (N = 45) by Belkin et al compared the picosecond 755-nm alexandrite laser, Q-switched ruby laser, Q-switched alexandrite laser, and Q-switched 1064-nm Nd:YAG laser for CALMs of the irregular-bordered “coast of Maine” subtype and the smooth-bordered “coast of California” subtype.^[16] The mean visual analogue scale (VAS) score was 3.67 for irregular-bordered lesions, an excellent average response (76-100% pigmentary clearance), compared with 1.76 for smooth-bordered lesions, a fair average response (26-50% clearance). These findings suggested that CALMS with jagged or ill-defined borders tend to respond better to laser treatment.

A 2023 systematic review by Guo et al assessed the efficacy of laser treatment of CALMs and compared clearance and recurrence rates for several laser types.^[20]  Overall, a clearance rate of 50% was achievable in 75% of patients, and a 75% clearance rate was achievable in 43.3%. The overall recurrence rate was 13%. The pooled hypopigmentation and hyperpigmentation rates were  both 1.2%. The best results were achieved with the Q-switched 1064-nm Nd:YAG laser. All of the laser types exhibited acceptable safety, with a low incidence of side effects (ie, hypopigmentation and hyperpigmentation).

A 2024 study (N = 14; mean age, 27.4 y) by Fernandez et al found the 730-nm picosecond titanium sapphire laser to be safe and effective for the treatment of CALMs in patients with Fitzpatrick skin types II-VI.^[21]  As in earlier studies, CALMs with "coast of Maine" morphology responded to laser therapy better than CALMs with "coast of California" morphology.

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